RO111192B1 - Process for the preparation of the clavulanic acid - Google Patents

Abstract

A process for the preparation and/or purification of clavulanic acid or a pharmaceutically acceptable salt thereof comprises i) contacting impure clavulanic acid or an alkali metal salt thereof in an organic solvent, with tertiary octylamine; ii) isolating the tertiary-octylamine salt of clavulanic acid formed; iii) converting the thus formed salt into clavulanic acid or a pharmaceutically acceptable salt or ester thereof.

Description

The present invention relates to a process for the preparation and / or purification of clavulanic acid of formula I:

CH OH

GUOH (I) or a pharmaceutically acceptable salt or ester thereof, usable as antibacterial agents, capable of enhancing the efficacy of penicillins and cephalosporins against β-15 lactamase-producing bacteria.

The preparation of clavulanic acid is known to be fermented by microorganisms that produce clavulanic acid, such as different microorganisms belonging to different networks of Streptomyces such as: S. clavuligerus NRRL 3585, S. jumoninensis NRRL 5741, S. katsurahamanus IFD 13716 and Streptomyces sp. . P 6621 FERM P28O4 2 5 [JP Kokai 80-162993). The resulting aqueous juice may be subjected to conventional purification and concentration processes, which involve, for example, filtration and chromatographic purification, 30 prior to extraction of the aqueous solution with an organic solvent, which produces a crude solution of clavulanic acid in organic solvent (GB). 1508977 and JP Kokai 80-62993).

The clavulanic acid salts can be obtained by absorbing the clavulanate anion from the filtered juice on an anion exchange resin, eluting it with an electrolyte, desalinating the resulting solution, submitting the desalinated solution 40 to another anion exchange resin. chromatographic elution with an electrolyte, desalination of the resulting solution and then removal of the solvent. This process can be used to give acceptable yields of pure material, but the use of resin columns involves many difficulties, which can limit large-scale production. An alternative process involving less than 50 stages of resin use is desirable.

It is known to prepare the clavulanic acid salts by precisely lithium clavulanate quenching (GB 1543563). Various amine salts of clavulanic acid are known as pharmaceuticals (GB 1578739). Tertiary butylamine salt of clavulanic acid (BE 862211) is known as a suitable ingredient for pharmaceutical formulations, but also as a useful intermediate in the preparation of clavulanic acid (EP 0026044). The use of tri (lower alkyl) -amine salts and dimethylamine salts of clavulanic acid is also known in a purification process for clavulanic acid, in which the triethylamine salt of clavulanic acid is formed, which is then transformed in the silyl diester of clavulanic acid (PT 94908). A process for purifying clavulanic acid is also known. wherein organic amines can be used to form an intermediate amine salt with clavulanic acid in an impure solution (EP, A, 0887178).

The process according to the invention, comprising the following steps: i) contacting impure clavulanic acid or a labile derivative thereof in an organic solvent solution, with an amine; ii) isolation of the amine salt of the clavulanic acid formed; iii) transforming the salt thus formed into clavulanic acid or a pharmaceutically acceptable salt or ester thereof, removes the disadvantages mentioned above, in that the amine is tertiary octylamine.

The process according to the invention has the advantage of obtaining faster acid and higher purity salts or esters.

In the process according to the present invention, the clavulanic acid salt with the amine can be used to purify the impure clavulanic acid during its preparation. Therefore, the salt can be formed in solution of clavulanic acid or its unstable derivatives, containing impurities, isolating the salt as a separate phase, for example, as a solid precipitate, from the solution containing residual impurities, then reforming the clavulanic acid or forming a salt or a pharmaceutically acceptable ester thereof.

RO 111192 Bl

Suitable unstable derivatives of clavulanic acid include, for example, salts of alkali metals, such as lithium or sodium clavulanate or esters such as silyl esters. Suitable unstable amine derivatives include salts such as: phosphate, borate, chloride, chlorate, perchlorate, bromide, toluenesulfonate or alkanates such as ethyl acetate or hexanoate. It is advantageous for the amine itself to come into contact with the impure clavulanic acid itself, in organic solvent solution.

The process according to the invention is suitably carried out in an organic solvent, which otherwise must be dried, for example, containing less than 6 g / 1, for example, 0.25 - 0.6 g / 1 water or may contains some water as a solvent of clavulanic acid and amine. An appropriate degree of drying can be achieved by a conventional water removal process, such as centrifugation. The water present in the solvent may be dissolved or dropwise as a separate phase.

The solution of clavulanic acid in organic solvent can be obtained by extraction of an aqueous, acidified solution of clavulanic acid, such as fermentation liquid. If the initial source of clavulanic acid is a slurry resulting from fermentation with microorganisms producing clavulanic acid, then to obtain a solvent extract of the appropriate concentration of clavulanic acid for use in this process, it is desirable not to extract it from the slurry itself, but at least some of the solids suspended in the groove are removed, for example, by filtration prior to extraction. It is also desirable, in addition, a preconcentration of the aqueous solution of clavulanic acid obtained by fermentation so that, for example, the aqueous solution of clavulanic acid is more often concentrated in acid than the initial juice, for example, preconcentration at a concentration of about 10-100 mg / ml, for example, 10-40 mg / ml, as well as 10 25 g / l clavulanic acid.

Suitable preconcentration processes include absorption of clavulanic acid in an anion exchange resin, followed by elution of clavulanic acid from it, with an aqueous electrolyte solution, such as sodium chloride and optional desarination. It is also preferred to acidify the aqueous solution, for example, juice or aqueous solution preconcentrated prior to solvent extraction, for example, at pH = 1 to 3. around pH = 1.5 to 2.5. It is also preferred to dry or remove water from the organic extraction solvent, before the formation of the amine salt, for example, at less than 6 g / l water. Preferably, the extraction is carried out at a temperature from 5 to 15 ° C.

Suitable organic solvents, in which impure clavulanic acid is brought into contact with octylamine, include hydrocarbon solvents such as toluene and hexane, ethers such as dichloromethane, dioxane, diethyl ether, halogenated solvents such as dichloromethane and chloroform, ketones such as acetone and methyl acetone acetone esters such as ethyl acetate. Solvents including a carbonyl group, for example those of formula: O

II 9

R - C - R in which R ^B is an alkyl group or an alkoxy group _7i and R ⁹ is an alkyl group are a sub-class of suitable solvents, for example organic ketones or organic alkanoate esters. The present invention also involves the use of mixtures of such solvents. A more suitable organic solvent is one that can be used directly in the extraction of acidified aqueous solution, for example, organic esters, alkyl alkanates, ketones and certain aliphatic alcohols or mixtures thereof, such as ethyl acetate, methyl acetate, acetate. of propyl, n-butyl acetate, methylethyl ketone, methylisobutyl ketone, tetrahydrofuran, butanol and mixtures of these solvents. Of these the most suitable may be methylisobutyl ketone, methylethyl ketone and ethyl acetate. Appropriate solvent mixtures include

EN 111192 Methyl ethyl ketone / methylisobutyl ketone and tetrahydrofuran / methylisobutyl ketone. A preferred solvent is ethyl acetate.

Suitable solvents for the amine include those set forth above, wherein the clavulanic acid may be dissolved or extracted, for example, acetone, ethyl acetate, methylisobutylketone and methylethylketone.

In particular, it seems preferable to include ketones, such as acetone, in the solvent system, as this seems to inhibit the formation of clavulanic acid salt with amine, as oil.

In general, an equivalent of an amine or a small excess of it per mole of clavulanic acid is used to produce the clavulanic acid salt. Clavulanic acid and amine solutions can, for example, be easily mixed with stirring and the mixture is stirred for a while until the addition is complete. The reaction between clavulanic acid and its unstable derivatives is recommended to take place at a temperature below ambient, for example, from O to 15 ° C, for example, O to 1O ° C or □ to 5 ° C. A suitable concentration of clavulanic acid or its unstable derivatives, in solution, is preferably at least 1 g / l, for example, the range from 1.0 to 4.0 g / l clavulanic acid. It may be advantageous to further concentrate the solvent extract at an excess concentration thereof, for example more than 20g / l.

Also, the amine can also be introduced by mixing in a jet of a solution of clavulanic acid in the solvent, so that the salt forms in the stream, either in solution or as particles or as droplets suspended by the dissolved salt in suspension. In this way, the amine can be introduced as such or as a solvent solution, for example, in the same organic solvent in which the clavulanic acid has been dissolved.

The desired clavulanic acid salt with the amine can then be isolated. In this way, the clavulanic acid salt with the amine is separated from most or all impurities. Isolation can be performed in a manner known, for example, by centrifugation or filtration.

In an alternative procedure for isolating the clavulanic acid salt with the amine, it may be isolated from the organic solvent, if the solvent is wholly or partially immiscible with water, by bringing the solvent into contact with water so as to extract the salt which may be in solution or in suspension, from the organic solvent and form an aqueous salt solution. As the clavulanic acid salt with the amine is readily soluble in water, such an aqueous solution can be highly concentrated, for example, around 20 ... 30% by weight.

In this way, the amount of organic impurities in the organic solvent solution remains in the organic solvent, while clavulanic acid, in the form of its amine salt, is obtained in a relatively pure state, in aqueous solution. The aqueous solution of the clavulanic acid salt thus formed may be subjected to subsequent treatment, for example, purification or conversion into clavulanic acid or pharmaceutically acceptable salt or ester.

By another further route or procedure, clavulanic acid and amine may be mixed in solution in a first organic solvent, then the salt may be separated from the solution by the addition of a second organic solvent. A suitable first organic solvent may be an organic ether, such as ethyl acetate, and a second solvent may be, for example, a halogenated solvent, such as chloroform, an ether, such as diethyl ether, a hydrocarbon such as toluene, an alcohol such as ethanol. or a solvent of the above formula, such as acetone or methylisobutyl ketone.

The clavulanic acid salt with the amine may be present as a solvent in acetone. In some cases acetone solvents have the advantage of stability and purity characteristics comparable to clavulanic acid salt with amine. Solvates can be isolated as a high purity and crystalline stable compound. During isolation and / or drying, some of the acetone may be lost, so the solvation power may not be higher, but the amount of acetone in the product does not become critical.

The acetone solvent can be formed by contacting clavulanic acid with *.

EN 111192 Bl Amine, in the presence of acetone. In general, a solution containing clavulanic acid may be mixed with at least the same volume of acetone. together with the amine, when the precipitation of the salt occurs.

The amine can be dissolved in acetone and mixed with a solution of clavulanic acid in an organic solvent. Preferred organic solvents include: ethyl acetate, tetrahydrofuran, methyl ethyl ketone and mixtures of such solvents, of which ethyl acetate is preferred. Alternatively, an aqueous solution of the clavulanic acid salt with amine, obtained by extraction in water, as mentioned above, may be mixed with acetone to form the solvate. Accordingly, a concentrated aqueous solution of the clavulanic acid salt with the amine, obtained by water extraction, may be mixed with acetone to form the solvate. Suitably, a concentrated aqueous solution of the salt may be mixed with excess acetone to form the solvate.

Recrystallization of clavulanic acid salt or acetone solvate may be advantageous by further reducing the level of impurities. A suitable solvent for recrystallization is the aqueous acetone solution. □ such recrystallization is carried out in the usual way, for example, the salt or solvate is dissolved in water, treated with a small amount of acetone, filtered and then treated with larger volumes of acetone, by stirring and / or optional cooling, to obtain the crystallized product.

Pharmaceutically acceptable salts of clavulanic acid include those of pharmaceutically accepted alkali or alkaline earth metals, for example, sodium, potassium and magnesium salts. Of these salts, the most appropriate are those of sodium and potassium, but those of potassium are preferred.

Suitable esters include those that are cleavable, capable of forming clavulanic acid or its salt by chemical methods, such as hydrogenolysis or biological methods.

Clavulanic acid salt with octylamine, optionally in the form of acetate solvate, can be converted to clavulanic acid or salt or ester, pharmaceutically acceptable, for example, by ionic substitution in the case of free acid or salts or by esterification.

Ion substitution can be produced using ion exchange resins, for example, by passing a salt solution through a cation exchange resin bed, in the form of sodium, potassium or calcium. Suitable cation exchange resins include Amberlite IR 20 or equivalent resins.

Alternative ion substitution may be effected by the reaction of the desecrated amino cation with a salt precursor compound, which may be a base, for example, a pharmaceutically acceptable bicarbonate or alkali or alkaline earth metal hydroxide or a carboxylic acid organic salt with a pharmaceutically acceptable cation, such as an alkaline or alkaline earth metal, for example, an alkanoic acid salt of the formula:

R ¹⁰ - CO H wherein, R ¹ ° is an alkyl group containing, for example, 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms. Examples of suitable salts include acetate, propionate or ethylhexanoate, preferably potassium 2-ethylhexanoate or sodium 2-ethylhexanoate. Specifically, the clavulanic acid salt with the amine in solution may react with an alkali metal salt, with acid in solution or in suspension, in a suitable solvent, which may be, for example, an organic solvent, water or mixture. of water with organic solvent, such as isopropanol. Appropriate solutions of clavulanic acid with the amine and the salt of the above compound can be mixed and the pharmaceutically acceptable salt can crystallize. The reaction may take place at a temperature below ambient, for example, from 0 ° C to 15 ° C, for example, from □ to 10 ° C, recommended at 0 ° C to 5 ° C. It is preferred that if the clavulanic acid salt with the tertiary amine is formed in aqueous solution, it is precipitated by mixing the solution

I>

Aqueous with excess acetone.

Examples of carrying out the process according to the invention are given below.

Example Π. In each case that follows, the procedure is identical. The amine is mixed with clavulanic acid in solution and a rapid crystallization with solid salt formation is observed.

The tertiary octylamine salt is in solid, crystalline, stable form, more than 70 h, at 20 ° C, 50% RH.

In the following, a clavulanic acid salt is formed with the amine, in the solution of a first organic solvent, and then proceeded to separation as a solid precipitate, by mixing with a second organic solvent.

a) Prepare an initial solution of clavulanic acid in ethyl acetate, containing about 28 g / l clavulanic acid, in impure form, by extraction of an impure S. clavuligerus, from a fermentation slurry, with ethyl acetate. To this ml, 0.84 g of tert-octylamine is added to 46 ml. After 10 min, the mixture becomes cloudy and the salt crystallizes into a fine crystalline form. An aliquot of chloroform solution is added, resulting in larger needles. To another aliquot is added acetone, again resulting in acicular crystals, but smaller and less rapid than with chloroform. To the remaining solution is added about 20 ml of chloroform, then a volume of toluene, equal to about the initial amount of solution, resulting in precipitation of an appreciable amount of acicular crystals.

b) To 500 ml initial solution, prepared as above, add 6.7 g of tert-octylamine. The solution becomes slightly cloudy. Add 20 ml of acetone, which clears the solution. An aliquot of diethyl ether solution is added, resulting in immediate crystallization. Add 55 ml diethyl ether to the main quantity of solution. The crystals are washed with acetone and filtered. The obtained quantity, 12.9 g, represents a 77% recovery of clavulanic acid from the solution.

Example 2. A solution of clavulanic acid in ethyl acetate of about 20 µg / ml is diluted with an equal volume of acetone. Then a solution of

1.25 mol equivalents of t-octylamine in acetone, dropwise, for 1/2 h, at 10 ° C. After stirring for 1 h, collect the precipitated crystals, wash with acetone and dry under vacuum. It forms relatively quickly, a white precipitate, with 76% yield (with purity correction).

Example 3. An impure solution of clavulanic acid, being a crude S. clavuligerus fermentation juice extract, after a prepurification by ion exchangers (500 ml; 21 µg / ml in ethyl acetate), containing additional 20 ml acetone, gradually treat with 7.6 g (1.0 g) toctilamine, producing a mild disorder. Addition of 55 ml of diethyl ether results in the separation of the amine salt as a white acrylic crystal, which is filtered and washed with acetone. 12.9 g are obtained, 77.2% recovery, 62.8% pfa (theoretically equal 60.6%).

Example 4. An impure solution of clavulanic acid being obtained from the fermentation juice of S. clavuligerus by prepurification involving chromatography with ion exchangers and generally described above, containing 7.1 g / l, was acidified to a pH 2 , 0 with 25% volume sulfuric acid and extracted continuously in ethyl acetate. The extract with ethyl acetate was cooled to 2 ° C, then dried by centrifugation, then treated with MgSO ₄ and finally passed through a column with CPG coal. In this phase the ethyl acetate extract contains 6.02 g / l clavulanic acid and is then concentrated by evaporation to a concentration of 25.7 g / l clavulanic acid, being used at this concentration. The moisture level of the concentrate is about 0.26% volumes.

Mix 7.8 ml of toctilamine with 25 ml of fresh ethyl acetate. This mixture is slowly added to 2 L of ethyl acetate extract, rich in clavulanate and diluted back to a titration of 23.0 g / l with fresh ethyl acetate, by rapid stirring. The slurry is stirred for another hour at 5 ° C. The t-octylamine clavulanate is subsequently isolated by filtration and washed with ethyl acetate.

RO 111192 Bl

The washing is continued with final drying, overnight, under vacuum, in an oven, at 2 ° C, under a stream of nitrogen.

Product weight 6.13 g.

Example 5. Dissolve 5 g of the amine salt produced in the above example in 97 ml isopropanol. The product did not completely dissolve and it was found necessary to apply a slight heating to 24 ° C, in order to produce a total dissolving effect. For 10 min, add 14 ml of 1.5 N. potassium 2-ethylhexanoate. The slurry is subsequently stirred for 1.5 h at 5 ° C. The potassium clavulanate is filtered, washed with small amounts of isopropanol, then with acetone and dried in a vacuum, overnight, in a nitrogen stream, at 20 ° C. The product is obtained by weight of 3.17 g.

Example S. Fermentation juice with filtered S. clavuligerus (RVP) containing 2 g / l clavulanic acid is acidified to pH 1.6 with 25% sulfuric acid by volume and extracted continuously in ethyl acetate. The solvent extract is cooled to 3 ° C, the water is removed by centrifugation, then dried with MgSO ₄ and passed through the CPG coal column. The carbon treated extract is then concentrated by evaporation to a clavulanic acid concentration of about 20 g / l, with a moisture content of about 0.06%, by volume.

Mix 13.5 ml of toctilamine with 43 ml of fresh ethyl acetate. This mixture is slowly added to 400 ml of clavulanate-rich extract in ethyl acetate, at a rate of 20 g / l clavulanic acid, with rapid stirring. The slurry is stirred for another hour at 5 ° C. The toctilamine clavulanate is then isolated by filtration and washed with ethyl acetate. The final drying takes place overnight, in a chamber, at 20 ° C, under vacuum, under a stream of nitrogen. The product is obtained in the amount of 12.44 g.

Example 7. Dissolve 11 g of amine salt, produced in the example above, in 213 ml of isopropanol. The product does not completely dissolve, even after light heating at 24 ° C. Introduced

3.75 ml of water to facilitate dissolution.

After the solution is obtained, additional 100 ml isopropanol is added to reduce the water content before crystallization.

Add 30 ml of 1.5 N potassium 2-ethylhexanoate in isopropanol for 15 minutes. The slurry is subsequently stirred for 1.5 h at 5 ° C. The clavulanate product of potassium is filtered, washed with small amounts of isopropanol, then with acetone and dried overnight under vacuum in a nitrogen stream at 20 ° C. The product is obtained in the quantity of 7.29 g.

Example 8. 20 g of benzyl clavulant (0.07 mol), purified by chromatography, was separated and dissolved in 400 ml of tetrahydrofuran and 5.7 g of palladium on 10% coal was added as catalyst. The mixture is hydrogenated with stirring at ambient temperature for 20 minutes. The way in which the reaction proceeds is studied by thin layer chromatography, using silica plates developed with ethyl acetate and visualized by using triphenyltetrazolium chloride reagent.

The reaction mixture is filtered and the filter holder is thoroughly washed with water. The combined filtrates (500 ml), containing clavulanic acid, are treated with shaking with 2-amino-2,4-trimethylpentane, in the amount of 9.0 g (0.07 mol) in 50 ml of dried tetrahydrofuran. crystallization occurs within 1 min. The mixture was stirred for 0.5 h at ambient temperature, then 2 h at 5 ° C. The product was filtered, washed with 100 ml of dry tetrahydrofuran and dried in vacuo for 12 h, yielding 23.0 g of salt, with a melting temperature of 160 ... 179 ° C.

Claims (36)

claims 1. A process for the preparation and / or purification of clavulanic acid, obtained by fermentation of a microorganism, a producer of clavulanic acid or a pharmaceutically acceptable salt or ester, comprising: i) contacting impure clavulanic acid or a a labile derivative thereof in an organic solvent, with an amine; ii) isolation of the amine salt of the clavulanic acid formed; iii) transforming the salt thus formed into acid Clavulanic Bl or a pharmaceutically acceptable salt or ester thereof, characterized in that the amine is tertiary octylamine. Process according to claim 1, characterized in that the labile derivative of clavulanic acid is an alkali metal salt. Process according to Claim 2, characterized in that the alkali metal salt is a sodium or lithium salt. Process according to any one of claims 1 ... 3, characterized in that the organic solvent is substantially dry. 5. Process according to claim 4, characterized in that the organic solvent contains less than 6 g / l water. 6. Process according to claim 4, characterized in that the organic solvent contains between 0.25 and 0.6 g / l water. Process according to any one of claims 4 ... 6, characterized in that the organic solvent is dried by dehydrating the solvent by centrifugation. Process according to any one of claims 1 to 7, characterized in that at least some solid products suspended in impure clavulanic acid, in the form of broth, are separated. A process according to claim 8, characterized in that the solids are separated by filtration. 10. Process according to any one of claims 8 or 9, characterized in that the aqueous solution of clavulanic acid obtained by fermentation is preconcentrated prior to extraction. Process according to claim 10, characterized in that the aqueous clavulanic acid solution is preconcentrated to a concentration of 10 ... 100 mg / ml. Process according to Claim 10, characterized in that the aqueous clavulanic acid solution is preconcentrated to a concentration of 10 ... 40 mg / ml. Process according to claim 10, characterized in that the aqueous clavulanic acid solution is preconcentrated to a concentration of 10 ... 25 mg / ml. 14. Process according to any one of claims 10 ... 13. characterized in that the preconcentration operation is performed by the absorption of clavulanic acid on an ion exchange resin, followed by the elution of the clavulanic acid therein, with an aqueous electrolyte solution. Process according to claim 14. characterized in that the electrolyte is sodium chloride. Process according to any one of claims * 14 or 15, characterized in that the resulting concentrate is desalted. Process according to any one of claims 7 to 16. characterized in that the broth or aqueous clavulanic acid solution is acidified prior to solvent extraction. The process according to claim 17, characterized in that the broth or aqueous clavulanic acid solution is acidified to a pH of 1 to 3. Process according to Claim 17, characterized in that the broth or aqueous clavulanic acid solution is acidified to a pH of from 1.5 to 2.5. Process according to any one of claims 1 ... 9, characterized in that the extraction of impure clavulanic acid or its labile derivative. In an organic solvent, it is carried out at a temperature from 5 to 15 ° C. Process according to any one of claims 1 ... 20, characterized in that the organic solvent used for the extraction of impure clavulanic acid or its labile derivative is selected from a group consisting of hydrocarbon solvents, halogenated solvents and ketone solvents. . . * RO 111192 Bl Process according to Claim 21, characterized in that the solvent is selected from a group consisting of toluene, hexane, tetrahydrofuran, dioxane, diethyl ether, dichloromethane, chloroform, acetone, methylisobutylketone and ethyl acetate. 23. Process according to any one of claims 1 to 22, characterized in that the octylamine and tertiary salt of clavulanic acid are formed by treating the impure clavulanic acid or its labile derivative, in an organic solvent, with an equivalent to a mole or with a slight excess of tertiary octylamine 15. Process according to claim 23, characterized in that the tertiary octylamine salt of clavulanic acid is obtained at Q up to 20 15 ° C. Process according to claim 23 or 24, characterized in that tertiary octylamine is introduced by mixing in a stream of clavulanic acid in organic solvent. Process according to any one of claims 1 ... 25, characterized in that the isolation of the tertiary octylamine salt of the clavulanic acid is accomplished by the extraction of the organic solvent containing the tertiary octilamine salt with water, for the extraction of the salt, followed by the transformation of the salt. of tertiary octylamine in clavulanic acid or a pharmaceutically acceptable salt or ester thereof. Process according to any one of claims 1 ... 26, characterized in that the tertiary octylamine salt of clavulanic acid is recrystallized. 28. Process according to claim 27, characterized in that the tertiary octylamine salt of clavulanic acid is recrystallized using acetone with water. The process according to any one of claims 1 ... 28, characterized in that the tertiary octylamine salt of clavulanic acid is converted into a pharmaceutically acceptable salt thereof, by ion exchange. Method according to claim 29, characterized in that the ion exchange is carried out by passing a tertiary octylamine salt solution through a bath with a cation exchange resin, in the form of sodium, potassium or calcium. 31. Process according to claim 29, characterized in that the ion exchange * is carried out by protonating the tertiary octylamine cation with a salt of the precursor compound. The process according to claim 31, characterized in that the salt of the precursor compound is potassium ethylhexanoate. Process according to any one of claims 29 ... 32, characterized in that the solvent is an organic solvent, water or a mixture of water and an organic solvent. 34. A process according to any one of claims 29 ... 32, characterized in that the reaction is carried out at a temperature below the ambient one. 35. Process according to claim 34, characterized in that the reaction is carried out at a temperature between 0 and 10 ° C. 36. Process according to claim 35, characterized in that the reaction is carried out at a temperature between 0 and 0.5 ° C.